The term “insomnia” broadly refers to an individual's report of difficulty sleeping. Insomnia has been defined in published literature as a disorder with the following diagnostic criteria: (1) Difficulty falling asleep, staying asleep or a lack of restorative sleep; (2) Persistence of sleep difficulties despite adequate opportunity and circumstances to sleep; (3) These sleep difficulties are associated with daytime impairment including cognitive, emotional or health effects; (4) Sleep impairment occurs at least 3 times per week for one month [1]. Studies estimate that 10% to 40% of American adults have intermittent insomnia and 10-15% have long-term sleep difficulties [2]. However, only approximately 5% of people with insomnia seek medical help. Cost estimates for lost productivity and insomnia-related accidents exceed $100 billion per year.
Due to its chronic nature, insomnia is associated with substantial impairments in the individual's quality of life. Individuals with insomnia score poorly on the 26-item Short Form Health Survey of the Medical Outcomes Study (SF-36) that broadly measures quality of life. One study compared the scores of patients with insomnia to those with depression and congestive heart failure and the results revealed that insomnia patients experienced a greater loss of function and increased emotional and mental health effects [3]. Several studies demonstrate a correlation between sleep deprivation and many conditions including weight gain, diabetes, depression and even an increased risk for mortality. In one published study, insomnia was associated with cognitive-emotional and cortical arousal and activation of the body's stress systems [4]. Insomnia has also been associated with decreases in work performance and increases in motor vehicle accidents and hospitalization rates [5].
According to the American Academy of Sleep Medicine (AASM) [6], a normal sleep pattern is characterized by 3 stages of non-rapid eye movement (NREM) sleep that each last between 5 and 15 minutes before REM sleep is attained, then the cycles repeat themselves. In stage 1 of NREM sleep, polysomnography readings show a reduction in wakefulness. This stage is characterized by light sleep that is easily interrupted and may also include a feeling of falling (called hypnic myoclonia). In stage 2, polysomnography shows positive and negative waves that are indicative of periods of muscle tone mixed with periods of muscle relaxation. Stage 3 is marked by deeper sleep known as slow-wave or delta sleep. Dreams can occur in Stage 3 NREM sleep, although the dreams tend to be less frequent and less memorable than those that occur during REM sleep. The next stage, REM (rapid eye movement) sleep is unlike the other sleep stages because the brain is very active. Insomnia may occur at any stage of sleep, having distinct effects depending on the nature of the disturbance. REM sleep is essential for emotional health and can be suppressed by medications such as anti-depressants. Stage 3 or slow-wave sleep is essential for physical rejuvenation and health of the immune system.
Causes of insomnia are highly variable and include the following: 1) Sleep disorders including sleep apnea and restless leg syndrome; 2) Illnesses such as asthma, congestive heart failure, hot flashes, arthritis and other causes of pain, gastrointestinal reflux disease; 3) Psychological medical conditions including depression and stress; 4) Neurological disorders including Parkinson's disease and dementia; 5) Stimulants such as caffeine and nicotine; 6) Medications including decongestants, certain anti-depressants, diuretics and beta blockers. Additionally, short-term difficulties with sleep that are not necessarily defined as “insomnia” can include inadequate opportunities for sleep; for example, caused by caring for a newborn or occupations that require long periods of alertness. Circadian rhythm sleep disorders are one of the major causes of insomnia. The suprachiasmatic nucleus in the brain is an intrinsic body clock that regulates bodily rhythms such as the sleep/wake cycle (circadian rhythm) (reviewed in [7]). The circadian clock is usually synchronized with the solar day such that cognitive function and energy levels are high in the daytime and sleep occurs at night. However, when an individual's sleep/wake pattern becomes misaligned with the body's circadian rhythm and the solar day, sleep disorders can occur. Among these are chronic insomnias, including delayed or advanced sleep phase syndrome, irregular sleep-wake cycles, and non-24-hour sleep-wake syndrome and insomnias that are temporary in nature; for example, due to jet lag or shift work. The circadian rhythm is regulated by secretion of N-acetyl-5-hydroxytryptamine (melatonin) from the pineal gland, which is induced at night and acts in the suprachiasmatic nucleus to facilitate sleep. There is evidence that circadian rhythms can be reset by phototherapy involving timed exposure to bright light [8]. Additionally, melatonin and melatonin receptor agonists have shown beneficial effects against insomnia; however, these treatments are not effective against mood disorders such as acute depression and major depressive disorder that are also associated with misaligned circadian rhythms [9].
Evaluation of insomnia includes a careful sleep history, review of medical history, review of medication use, family history, and screening for depression, anxiety and other possible variables affecting sleep. A physical examination is necessary to assess the presenting symptoms, if any. These symptoms might include snoring (possible sleep apnea), peripheral edema (heat failure), mental status (anxiety, substance abuse) or asthma. Diagnostic tests can be performed to evaluate thyroid function, abnormal hormone levels, elevated serum glucose, uremia, and iron deficiency (which could be indicative of restless legs syndrome or periodic limb movement disorder). An important diagnostic tool for insomnia is polysomnography, a diagnostic test in which physiologic sensors are place on the patients during sleep to record brain electrical activity, eye and jaws muscle movement, leg muscle movement, airflow, respiration, EKG, and oxygen saturation. One or more of these diagnostic criteria could be useful for directing an affected individual toward use of the nutraceutical composition disclosed in the present invention.
In cases where insomnia is short-term or unrelated to medical circumstances, lifestyle modifications can be implemented to aid sleep. Healthy sleep habits include maintaining a regular sleep-wake schedule and avoidance of stimulants, alcohol, and caffeine 4-6 hours before bedtime. Environmental factors such as eliminating noise, maintaining a comfortable room temperature and minimizing light are also important for promoting sleep. Stress management and relaxation therapy can also be helpful for some patients. Pharmacological approaches for inducing sleep have been centered around the activation of GABA, one of the major inhibitory neurotransmitters in the central nervous system. Drugs that have been designed to activate GABA receptors include hypnotic drugs: barbiturates, benzodiazepines, imidazopyridines, and cyclopyrrolones. Benzodiazepines are considered first-line treatments for anxiety disorders and for insomnia (temazepam [Restoril], flurazepam [Dalmane], triazolam [Halcion], estazolam [ProSom], and lorazepam [Ativan]). Benzodiazepines selectively target GABA(A) receptors that contain the alpha1, alpha2, alpha3, or alpha5 subunits, which promote sleep when stimulated [10]. Insufficient release of GABA in the brain can also lead to depression, anxiety and other mood disorders having similar symptoms of chronic insomnia. GABA is normally released during the early stages of the sleep cycle, which facilitates relaxation and restful sleep in the subsequent stages of sleep. Despite their widespread clinical use, use of benzodiazepines carries the risk of drug dependence. Moreover, these medications can have several undesirable side effects including amnesia, irritability, impaired judgment, tolerance and physical dependence. Other treatment options for insomnia are nonbenzodiazepines including zaleplon [Sonata], zolpidem [Ambien], and eszopiclone [Lunesta]). These drugs decrease sleep latency and the number of awakenings by targeting the gamma aminobutyric (GABA) receptor. The side effects of nonbenzodiazepines include drowsiness, dizziness, headache, diarrhea, nausea, and dry mouth. Sedating antidepressants (trazodone [Desyrel], mirtazapine [Remeron], paroxetine [Paxil]) can be useful if the patient is also diagnosed with depression. Ramelteon (Rozerem) is another sleep-promoting drug that is a melatonin receptor agonist that acts on receptors that regulate the sleep-wake cycle. Possible side effects of melatonin receptor agonists include nausea, dizziness, fatigue, somnolence, aggressive behavior, agitation, behavioral changes, and hallucinations. In light of the potential side effects of drugs for treating insomnia, herbal remedies that offer the possibility of having fewer unwanted side effects are also an option.
Pain represents one of the primary underlying causes of sleep disturbances. There is a circular relationship between insomnia and pain, such that pain leads to sleep disorders and sleep disorders increase the perception of pain [11]. Numerous published studies show that lack of sleep has hyperalgesic effects in intensifying pain perception [12, 13]. Insomnia associated with pain is considered to be an under-reported, under-diagnosed and under-treated problem that often symptomatic of other underlying medical and psychological causes [11]. In one study, for example, the severity of depression among veterans was independently associated with poor sleep quality and more severe pain [14].
Medications for addressing pain can have undesirable effects on sleep; therefore, treatments must be carefully considered when individuals present with both conditions. For example, certain over-the-counter medications, particularly those containing caffeine (for example, Excedrin® (formulation containing acetaminophen, aspirin and caffeine, sold by Novartis), Anacin® (formulation containing aspirin and caffeine, sold by Prestige Brands Holdings, Inc.), and Motrin Complete® (ibuprofen, sold by Johnson & Johnson Consumer Inc.)), can interfere with sleep. Narcotic pain medications, used to treat moderate to severe pain, are associated with poor sleep quality. For example, a published study reported a high rate of sleep impairment and poor sleep quality in people with prescription opiod dependence [15]. This study also demonstrated that the severity of pain, as measured by self-reporting, was correlated with poor sleep quality. Alternatively, sleep-promoting and pain medications can have additive effects, which increases the risk of side effects and adverse reactions, including excessive drowsiness and poor cognitive function the following day.
Disclosed in the present invention is a composition of ingredients that possess sleep-promoting and anti-anxiety effects, as well as methods for administering said composition to promote sleep and to reduce anxiety.